1. Field of the Invention
The present invention relates to methods for enhancing female sexual desire and responsiveness. The present method also relates to compositions and kits useful for enhancing female sexual desire and responsiveness.
2. Discussion of the Background
The female sexual response cycle can be divided into the four following phases (as adapted from Diagnostic and Statistical Manual IV, xe2x80x9cSexual and Gender Identity Disorder,xe2x80x9d American Psychiatric Association, Washington, D.C., pp. 493-494 and 735-751, 1994:
1. Desire, which includes fantasies about sexual activity and the desire to have sexual activity;
2. Excitement, which consists of subjective senses of sexual pleasure and accompanying physiological changes including vasocongestion in the pelvis, vaginal lubrication, and expansion and swelling of the external genitalia;
3. Orgasm, which consists of peaking of sexual pleasure with release of sexual tension; and
4. Resolution, which consists of a sense of muscular relaxation and general well-being.
Disorders of female sexual desire or response are estimated to affect from 30 to 50 percent of the adult population in various studies (see, e.g., S. G. Nathon, xe2x80x9cThe Epidemiology of the DSM-III Psychosexual Dysfunctions,xe2x80x9d J. of Sex and Marital Therapy, vol. 12, no. 4, pp. 267-281 (1986); Diagnostic and Statistical Manual IV, xe2x80x9cSexual and Gender Identity Disorder,xe2x80x9d American Psychiatric Association, Washington, D.C., pp.493-539, 1994; M. Osborn et al, xe2x80x9cSexual dysfunction among middle aged women in the community,xe2x80x9d British Medical Journal, vol. 296, pp. 959-962 (1988); E. Frank et al, xe2x80x9cFrequency of Sexual Dysfunction in xe2x80x9cNormal Couplesxe2x80x9d,xe2x80x9d New England Journal of Medicine, vol. 299, pp. 111-115 (1978); and K. Garde et al, xe2x80x9cFemale sexual behavior: a study in a random sample of forty-year-Old Danish Women,xe2x80x9d Maturitas, vol. 2, pp. 225-240 (1980)). These very common disorders may have a variety of causes including psychogenic etiologies, anatomical disorders, drug-induced disorders, diabetes mellitus, post-surgical disorders, atherosclerosis, post-traumatic disorders, as well as endocrine etiologies.
The search for effective pharmacologic treatments to influence sexual behavior has been a preoccupation of all societies throughout history (see, e.g., E. L. Abel, Psychoactive Drugs and Sex, Plenum Press, New York, 1985; and J. Buffum, xe2x80x9cSubstance abuse and high-risk sexual behavior,xe2x80x9d J. Psychoact. Drugs, vol. 20, pp.165-168 (1988)). In one of the few scientific review articles on this topic (R. C. Rosen et al, xe2x80x9cProsexual Drugs: Empirical Status of the xe2x80x9cnew Aphrodisiacsxe2x80x9d,xe2x80x9d Archives of Sexual Behavior, vol. 22(6), pp.521-543 (1993)), Rosen states: xe2x80x9cIn particular, the search for the perfect aphrodisiacxe2x80x94a drug that will heighten sexual desire, pleasure and performance has been a continuing cultural quest from ancient to modern times. Natural substances such as datura, belladonna and henbane were key ingredients in the sexual orgies of ancient fertility cults. Yohimbine has long been used by the natives of Africa to enhance their sexual prowess, as was the mandrake plant in medieval Europe (E. L. Abel, Psychoactive Drugs and Sex, Plenum Press, New York, 1985). Oysters, ginseng and Vitamin E have similarly been recommended at various times as possessing aphrodisiacal qualities (R. C. Rosen et al, Sexuality, Random House, New York, 1984). Given the perennial search for an effective aphrodisiac, it is surprising that relatively few drugs have been demonstrated to have specific prosexual properties.xe2x80x9d
L-dopa has been reported to stimulate sexual responsiveness in male and female patients. However, subsequent studies have yielded inconsistent or contradictory results regarding the effect of L-dopa on sexual behavior (M. Hyppa et al, xe2x80x9cIs L-dopa an aphrodisiac in patients with Parkinson""s disease?,xe2x80x9d in Sexual Behavior Pharmacology and Biochemistry, M. Sandler et al, Eds., Plenum Press, New York, 1975; and O. Benkert et al, xe2x80x9cEffect of L-dopa on sexually impotent patients,xe2x80x9d Psychopharmacologia, vol. 23, pp. 91-95 (1972)). Most of these studies deal exclusively with men and extremely few studies have even mentioned women. Apomorphine has been investigated for erectile dysfunction in men, but there have been no positive reports in women. Nomifensine and bupropion which are atypical anti-depressants acting on dopamine have been reported to have stimulatory effects on females with decreased sexual desire (S. Lal et al, xe2x80x9cApomorphine induced penile tumescence in impotence patientsxe2x80x94preliminary findings,xe2x80x9d Prog. Neurol. Psychopharmacol. Biol. Psychiat., vol. 11, pp. 235-242 (1987). Subsequent studies by Klein et al did not replicate these effects (K. B. Klein et al, xe2x80x9cDrug treatment of patients with inhibited sexual desire: A controlled clinical trial,xe2x80x9d presented at the SSTAR annual meeting, New Orleans, 1987).
Prostaglandins may have a possible role in human ovulation (G. M. Craig, xe2x80x9cProstaglandins in reproductive physiology,xe2x80x9d PMJ, vol. 51, pp. 74-84 (1975)). Prostaglandin E1 (PGE-1), prostaglandin E2 (PGE-2), and prostaglandin F2xcex1 (PGF-2xcex1) cause uterine contraction in women. Indeed, PGE-2 is presently used in the United States for inducing labor and cervical ripening.
Present therapies for disorders of sexual response and desire include various types of psychotherapeutic counseling (J. LoPiccolo et al, xe2x80x9cTreatment of Sexual Dysfunction,xe2x80x9d J. of Counseling and Clinical Psychology, vol. 54(2), pp. 158-167 (1986)). There is also a report of using electrical stimulators placed inside the vagina to induce orgasms (see: D. Boutos, xe2x80x9cApparatus for stimulating penile, scrotal, anal, vaginal, and clitoral tissue,xe2x80x9d U.S. Pat. No. 5,571,118). Neither of these methods are particularly desirable or effective in treating these disorders.
Thus, there remains a need for a method for enhancing female sexual desire and responsiveness. There also remains a need for pharmaceutical compositions and kits useful for enhancing female desire and responsiveness.
Accordingly, it is one object of the present invention to provide novel methods for enhancing female sexual desire and responsiveness.
It is another object of the present invention to provide novel pharmaceutical compositions which are useful for enhancing female sexual desire and responsiveness.
It is another object of the present invention to provide novel kits useful for enhancing female sexual desire and responsiveness.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor""s discovery that application of a prostaglandin directly to the clitoris of a female is effective for enhancing female sexual desire and responsiveness.
Thus, in a first embodiment, the present invention provides novel methods for enhancing female sexual desire and responsiveness. In the context of the present invention, the term enhancing female sexual desire and responsiveness includes the treatment of disorders of female sexual desire and/or response. The term disorders of female sexual desire and/or response means any disorder which causes a decrease in or absence of female sexual responsiveness or female sexual desire. This includes any persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity. It also includes decreases in the physiological response to sexual stimulation such as slowed or decreased erectile response of the female erectile tissues; slowed, decreased or absent lubrication of the vagina; slowed, decreased, or absent ability to have orgasms; decreased intensity of or pleasure in orgasms; frigidity; sexual aversion; and disorders of female sexual desire and response that are secondary to a general medical condition such as the menopausal or post-menopausal state, radiotherapy of the pelvis, atheroscelerosis, pelvic trauma or surgery, peripheral neuropathies, autonomic neuropathies, diabetes mellitus, and disorders of the innervation of any of the sexual organs. This term also includes substance-induced sexual dysfunction including but not limited to decreases in desire and responsiveness secondary to anti-depressants, neuroleptics, anti-hypertensives, opiates, alcohol and any other drug found to decrease or eliminate any part of the sexual response cycle. Primary and secondary anorgasmia are included. Vaginismus (a psychologically induced spasm of the vagina) may be resistant to the present method and compositions.
Specifically, the present method involves application of a prostaglandin directly to the clitoris. Examples of suitable prostaglandins include PGE-1; PGE-2; PGF-2xcex1; PGA-1; PGB-1; PGD-2; PGE-M; PGF-M; PGH-2; PGI-2; 19-hydroxy-PGA-1; 19-hydroxy-PGB-1; PGA-2; PGB-2; 19-hydroxy-PGA-2; 19-hydroxy-PGB-2; PGB-3; PGF-1xcex1; 15-methyl-PGF-2xcex1; 16,16-dimethyl-xcex942-PGE-1 methyl ester; 15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; 16,16-dimethyl-PGE-2; 11-deoxy-15-methyl-PGE-1; 16-methyl-18,18,19,19-tetrahydrocarbacyclin; (16RS)-15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; (+)-4,5-didehydro-16-phenoxy-xcex1-tetranor-PGE-2 methyl ester; 11-deoxy-11a, 16,16-trimethyl-PGE-2; (+)-11a, 16a,b-dihydroxy-1,9-dioxo-1-(hydroxymethyl)-16-methyl-trans-prostene; 9-chloro -16,16-dimethyl-PGE-2; arboprostil; and semisynthetic or synthetic derivatives of these natural prostaglandins, or any derivative or any prostaglandin analog capable of acting as a vasodilator or neuromodulator. Cyclodextrin complexes are also included as they may enhance the activity of the solution and stabilize the prostaglandin. Racemic, optically enriched or purified stereoisomers of any of these compounds are also included. Physiologically acceptable salts are also included. Preferably, the prostaglandin is PGE-1, PGE-2, PGF-2xcex1, PGD-2, PGF-1xcex1, and 15-methyl-PGF-2xcex1. Most preferably, the prostaglandin is PGE-2 or PGE-1.
Preferably, the prostaglandin is administered topically, directly to the clitoris. Administration topically to the clitoris may be accomplished by applying an amount of a liquid, gel, or solid which contains an effective amount of the prostaglandin directly onto the clitoris. In the case when the prostaglandin is contained in a pharmaceutical composition which is a liquid, the administration may be accomplished by means of a dropper or syringe. The liquid solution may also be sprayed or delivered in an aerosol onto the clitoris. When the composition containing the prostaglandin is in the form of a gel, lotion, or cream the administration may be carried out by means of a tube, brush, swab or the finger tip. Pharmaceutical compositions which contain the prostaglandin and which are in the form of a solid may be administered by placing the appropriate amount of the solid directly on the clitoris or by dusting or spraying a powder.
Although the exact amount of prostaglandin to be administered will depend on the exact size and condition of the patient, the prostaglandin is suitably administered in an amount of 0.1 nanograms to 2,000 xcexcg, preferably 1.0 nanogram to 500 xcexcg. Specifically, when the prostaglandin is PGE-1, the PGE-1 is suitably administered in an amount of 20 nanograms to 2,000 xcexcg, preferably 200 nanograms to 500 xcexcg, per unit dosage. When the prostaglandin is PGE-2, the PGE-2 is suitably administered in an amount of 0.1 nanograms to 2,000 xcexcg, preferably 1 nanogram to 500 xcexcg, per unit dosage. These broad ranges of suitable dosages reflect clinical findings that various coagents and carriers can either increase or decrease the drug activity exhibited by a given mixture.
Typically, the prostaglandin will be administered 1 to 60 minutes, preferably 5 to 30 minutes, prior to the time when it is desired to commence sexual intercourse.
PGE-1, prostaglandin E1, is also known as alprostadil or PGE1. The formal chemical name of PGE-1 is 3-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneheptanoic acid, and the structure of PGE-1 is 
Prostaglandin E1 may be isolated from sheep seminal vesicle tissue as described in Bergstrom et al., Acta. Chem. Scand., vol. 16, p. 501 (1962) and J. Biol. Chem., vol. 238, p. 3555 (1963). The synthesis of prostaglandin E1 may be carried out as described in Corey et al., J. Am. Chem. Soc., vol. 91, p. 535 (1969); Corey et al., J. Am. Chem. Soc., vol. 92, p. 2586 (1970); Sih et al, J. Am. Chem. Soc., vol. 94, p. 3643 (1972); Sih et al., J. Am. Chem. Soc., vol. 95, p. 1676 (1973); Schaaf et al., J. Org. Chem., vol. 37, p. 2921 (1974); and Slates et al., Tetrahedron, vol. 30, p. 819 (1974).
PGE-2, prostaglandin E2, is also known as dinoprostone or PGE2. The formal chemical name of PGE-2 is 7-[3-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid, and the structure of PGE-2 is: 
Prostaglandin E2 may be isolated from sheep seminal vesicle tissue as described in Bergstrom et al., Acta. Chem. Scand., vol. 16, p. 501 (1962). Prostaglandin E2 may be synthesized as described in Corey et al., J. Am. Chem. Soc., vol 92, p. 397 (1970); Corey et al., J. Am. Chem. Soc., vol. 92, p. 2586 (1970); and Heather et al., Tetrahedron Letters, p. 2313 (1973).
Both prostaglandin E1 and E2 are commercially available from Sigma Chemical Company of St. Louis, Mo.
PGE-2 is also commercially available as a Prostin E-2 suppository and as Prepidil Gel from Pharmacia and UpJohn Company, Kalamazoo, Mich., and as Cervidil from Forrest Pharmaceuticals, Inc., St. Louis, Mo. These preparations are indicated for cervical ripening and contain between 0.5 and 20 mgs of PGE-2. No reports in the medical literature, Physicians Desk Reference, 51st Edition, Medical Economics, Montvale, N.J., 1997; or Goodman and Gillman""s The Pharmacologic Basis of Therapeutics, 9th Edition, McGraw-Hill, 1996 can be found with respect to prostaglandins stimulating the female sexual response. Indeed, in labor induction as much as 1000-10,000,000 times the dose effective in the present method of PGE-2 is administered to the cervix without sexual stimulation ever being reported as a side effect.
PGF-2xcex1, prostaglandin F2xcex1, is also known as dinoprost or PGF2xcex1. The formal chemical name is 7-[3,5-dihydroxy-2-(3-hydroxy-1-octenyl)cyclopentyl]-5-heptenoic acid. PGF-2xcex1 may be prepared as described in U.S. Pat. No. 3,657,327, which is incorporated herein by reference.
15-Deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester is also known as misoprostol and has the formal chemical name of (xc2x1)-methyl-(1R,2R,3R)-3-hydroxy-2-[(E)-(4RS)-4-hydroxy-4-methyl-1-octenyl]-5-oxocyclopentaneheptanoate. 15-Deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester may be prepared as described in U.S. Pat. No. 3,965,143, which is incorporated herein by reference.
Enprostil has the formal chemical name of [1xcex1,2xcex2(1E,3R*),3xcex1]-7-[3-hydroxy-2-(3-hydroxy-4-phenoxy-1-butenyl)-5-oxocyclopentyl]-4,5-heptadienoic acid methyl ester. Enprostil may be prepared as described in U.S. Pat. No. 4,178,457, which is incorporated herein by reference.
PGI-2 is also known as prostacyclin, epoprostenol, prostaglandin I2, prostaglandin X, PGI2, and PGX. Prostacyclin may be prepared as described in U.S. Pat. No. 4,539,333, which is incorporated herein by reference.
The remaining prostaglandins are described in Alex Gringanz, Introduction to Medicinal Chemistry, Wiley-VCH, Inc., New York, pp. 158-159 and 641-642, 1997, which is incorporated herein by reference.
Cyclodextrin complexes of the prostaglandin may be used in order to increase the stability and efficacy. Cyclodextrin complexes may be prepared by adding the proper stoichiometric ratio of the prostaglandin to xcex1, xcex2, or xcex3 cyclodextrin in an aqueous solvent and then either using as is or lyophilizing to provide a solid clathrate for mixing. These complexes are described in Yamamura et al, J. Chromatogr., vol. 331, pp. 383-388 (1985); Hirayama et al, Chem. Pharm. Bull., vol. 32 pp. 4237-4240 (1984); Uekama et al, J. Pharm. Sci., vol. 73, pp. 382-384 (1984); and Yamamura et al, J. Chromatogr., vol.303, pp. 165-172 (1984), which are incorporated herein by reference.
The prostaglandin may be administered alone or it may be advantageous to simultaneously administer or to pretreat the patient with one or more co-agents to increase the efficacy of the method. Examples of co-agents which may be coadministered include:
1. Agents which inhibit 15-hydroxyprostaglandindehydrogenase (PGDH);
2. ACE inhibitors, including but not limited to captopril, enalapril, enalaprilat, quinapril, lisinopril, and ramipril, may enhance the efficacy of the present method and decrease long term complications, such as inflammatory and fibrotic responses;
3. Nitro vasodilators, including but not limited to nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide mononitrate, erythrityl tetranitrate, and sodium nitoprusside, may enhance the efficacy of the present method;
4. Alpha blockers, including but not limited to prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin, trimazosin, tolazoline, corynthanine, rauwolscine, and piperoxan, are especially desirable for increasing the efficacy and prolonging the action of the present method;
5. Other adrenoreceptor agents, including but not limited to yohimbine, labetalol, carvedilol, and bucindolol, may also enhance the activity and prolong the action of the present method;
6. Phosphodiesterase (PDE) inhibitors, including but not limited to caffeine, aminophylline, theophylline, amrinone, milrinone, vesnarinone, vinpocetine, pemobendan, cilostamide, enoximone, peroximone, rolipram, R020-1724, zaniprast, dipyridamole, and sildenafil, may also be effective in enhancing the efficacy of the present method and for prolonging the effect;
7. Muscarinic agents such as pilocarpine, edrophonium, and bethanacol;
8. Dopaminergic agonists such as apomorphine and bromocriptine;
9. Ergot alkaloids such as ergotamine and ergotamine analogs, including acetergamine, bravergoline, bromerguride, clanegollone, ergonovine, ergotamine tartrate, and pergolide;
10. Opiate antagonists such as naloxone, naltrexone, nalmefene, nalorphine, methyl naltrexone, CTOP, diprenorphine, xcex2-funaltrexamine, naloxonazine, nor-binaltorphimine, natrindole, BNTX, and other analogs, which exhibit opioid antagonistic properties; and
11. Polypeptide neurotransmitters such as VIP, calcitonin, calcitonin gene related product, VIP analogs, and cholecystokinin and all its analogs such as CCK8.
Particularly desirable combinations are PGE and alpha-blockers, PGE and PGDH inhibitors, and PGE and PDE inhibitors. Any combinations of the single above-listed compounds or multiple combinations of different compounds or different groups may also be used. In some instances, it may be advantageous to pretreat with one or more of the co-agents. For example, pretreatment with a PGDH inhibitor followed by treatment with PGE will enhance the efficacy of the present method.
By the term xe2x80x9c15-hydroxyprostaglandindehydrogenase inhibitorxe2x80x9d it is meant any compound which exhibits a significant and selective inhibition of prostaglandin degrading enzyme, or 15-hydroxyprostaglandindehydrogenase (PGDH). Two forms of 15-hydroxyprostaglandindehydrogenase (PGDH) are known: Type I, which is NAD+ dependent, and Type II, which is NADP+ dependent. Type I operates at a Km one order of magnitude lower than Type II and is thus more significant physiologically. Type I PGDH is described in Mak et al, Biochimica et Biophysica Acta, vol. 1035, pp. 190-196 (1990); Ensor et al, J. Lipid Mediators Cell Signalling, vol. 12, pp. 313-319 (1995); and Berry et al, Biochemical Pharmacology. vol. 32, no. 19, pp. 2863-2871 (1983), which are incorporated herein by reference. Partially purified bovine lung Type I PGDH is commercially available from BDH, Limited (Poole, UK). Berry et al., Tai et al., Muramatsu et al., and Mak et al. describe assays for determining enzymatic activity of Type I PGDH as well as methods for determining the degree of inhibition of this enzyme.
Type II PGDH is described in Chang, et al, Biochem. Biophys. Res. Commun., vol. 99, pp. 745-751 (1981); Jarabak, et al, Prostaglandins, vol. 18, pp. 241-246 (1979), and et al, Biochem. Biophys. Res. Commun., vol. 81, pp. 1227-1234 (1978), all of which are incorporated herein by reference.
Examples of suitable 15-hydroxyprostaglandindehydrogenase inhibitors include but are not limited to glycyrrhizic acid, licorice, glycyrrhetinic acid, various glycosides of glycrrhetinic acid, carboxenolone, DHEA, spironolactone, sofalcone, indomethacin, sulindac, etodolac, oleic acid, palmitic acid, and sulphasalazine and analogues thereof. Antibodies which bind to and inhibit Type I PGDH may also be used.
Glycyrrhizic acid is also known as glycyrrhizin, glycyrrhizinic acid, and glycyrrhetinic acid glycoside. The formal chemical name is 20xcex2-carboxy-11-oxo-30-norolean-12-en-3xcex2-yl-2-O-xcex2-D-glucopyranuronosyl-xcex1-D-glucopyranosiduronic acid, and the structure is: 
Glycyrrhizic acid is commercially available from Sigma Chemical Company of St. Louis, Mo.
Glycyrrhetinic acid is unglycosylated glycyrrhizic acid, and its structure is: 
Glycyrrhetinic acid may be obtained from licorice extract.
Carbenoxolone is also known as 3xcex2-hydroxy-11-oxo-20xcex2-olean-12-en-29-oic acid hydrogen butanedioate and has the following structure: 
Carbenoxolone may be synthesized as described in U.S. Pat. No. 3,070,623, which is incorporated herein by reference.
Licorice is also known as sweet root liquorice and glycyrrhiza and is described in the Merck Index, 10th edition, citation 4368 as xe2x80x9cglycyrrhiza, Licorice, liquorice; sweet root. Dried rhizome and root of Glycyrrhiza glabra L., var. typica Regel and Herder (Spanish licorice), or of G. Glabra L., var. glandulifera (Waldst. and Kit.) Regel and Herder (Russian licorice), or of other varieties of G. g yielding a yellow and sweet wood, Leguminosaw. Habt. Southern Europe to Central Asia. Constit. 6-14% glycyrrhizin (the glucoside of glycyrrhetic acid), asparagine, sugars, resin.xe2x80x9d
Licorice is a crude preparation prepared from dried rhizomes or roots and as such contains large numbers of compounds many of which are not identified. A simple aqueous extract of a commercially available dried licorice root preparation may be prepared as follows. Two grams of this dried licorice root was mixed with 10 mls of distilled water, stirred until thoroughly mixed at room temperature and filtered to remove particulate matter. This simple aqueous extract of licorice is effective in inhibiting PGDH and may be used as is in the present invention.
Spironolactone is also known as Aldactone A or Verospiron. The formal chemical name of spironolactone is 17-hydroxy-7-mercapto-3-oxo-17xcex1-pregn-4-ene-21-carboxylic and xcex3-lactone, 7-acetate, and the structure is: 
Spironolactone is commercially available from Sigma Chemical Company of St. Louis, Mo.
Sofalcone is formally known as [5-[(3-methyl-2-butenyl)oxy]-2-[3-[4[(3-methyl-2-butenyl)oxy]phenyl]-1-oxo-2-propenyl]phenoxy]acetic acid and has the formula: 
Sofalcone may be prepared as described in U.S. Pat. No. 4,085,135, which is incorporated herein by reference.
DHEA is formally known as 3-hydroxyandrost-5-en-17-one or dehydroepiandrosterone or prasterone. The structure of DHEA is: 
DHEA may be prepared as described in H. Hosoda et al, J. Org. Chem., vol. 38, p. 4209 (1973), which is incorporated herein by reference.
Sulfasalazine is also known as 2-hydroxy-5[[4-[(2-pyridinylamino)sulfonyl]phneyl]azo]benzoic acid and has the structure: 
A number of sulfasalazine analogs have been shown to be inhibitors of PGDH by Berry et al, Biochemical Pharmacology, vol. 32, pp. 2863-2871 (1983). Examples of sulfasalazine analogs which may be used as the PGDH inhibitor in the present compositions include: 
Etodolac is also known as 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. Etodolac may be prepared as described U.S. Pat. No. 3,843,681, which is incorporated herein by reference.
Indomethacin is also known as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. Indomethacin may be prepared as described in U.S. Pat. No. 3,161,654, which is incorporated herein by reference.
Sulindac is also known as 5-fluoro-2-methyl-1-[[4-methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. Sulindac may be prepared as described in U.S. Pat. Nos. 3,654,349 and 3,647,858, which are incorporated herein by reference.
The 15-hydroxyprostaglandindehydrogenase inhibitor will typically be present in an amount of 25 to 100, preferably 50 to 100, pig clitoral units of PGDH inhibition activity, per unit dosage. The amount of inhibitor which corresponds to a unit of pig clitoral PGDH inhibition activity is determined using either the spectrophotometric or radio-chemical assay described in the Examples. For inhibitors which exhibit a significant absorption at 340 nm, it is preferred to use the radio-chemical assay.
In a second embodiment, the present invention provides novel pharmaceutical compositions which are useful for enhancing female sexual desire and responsiveness. The present pharmaceutical compositions are characterized as containing: (a) a prostaglandin; (b) a pharmaceutically acceptable carrier; and having a pH of 3 to 7, preferably 4 to 6. In cases in which an aqueous component is present, one may simply add a sufficient amount of a pharmaceutically acceptable acid or base, e.g., HCl or NaOH to adjust the pH to the desired value. For nonaqueous compositions, one may add to each unit dose the residual powder from 0.5 ml of a 0.01 Molar aqueous solution of a pharmaceutically acceptable citrate salt, e.g., sodium citrate, which has the desired pH. For example, 0.5 ml of 0.01 Molar sodium citrate at pH 4.5 is lyophilized, and the powdered residue is added to a unit dose of PGE-2 in polyethylene glycol (PEG) MW 1450. Upon contact of this dose with a mucosal membrane, the lyophilized citrate will dissolve and buffer the pH of the mucosal fluid to about pH 4.5 and thereby enhance the activity of the PGE-2 as the PEG pellet dissolves.
In a preferred embodiment, the present composition further comprises: (c) an antioxidant selected from the group consisting of citrate salts and tocopherol. It has been found that prostaglandins, in particular PGE-2, are especially stabile when formulated in a composition which contains a citrate salt, such as sodium, potassium, or ammonium citrate, or tocopherol. Typically, the present pharmaceutical composition will contain 1 to 2,000 xcexcg, preferably 50 to 1,000 xcexcg, of the citrate salt, or 20 to 2,000 xcexcg, preferably 50 to 1,000 xcexcg, of tocopherol. Particularly good results have been achieved when the prostaglandin is present in a 1 millimolar sodium citrate aqueous solution or in liposomal solution which also contains 1 mg per ml of tocopherol as an antioxidant.
The present compositions may also contain the same coagents described above in the context of the present method. Thus, the present compositions may contain one or more agents which block prostaglandin degrading enzymes, one or more ACE inhibitors, one or more muscarinic agents, one or more adrenoreceptor agents, one or more dopamine agonists, one or more opiate antagonists, one or more nitrates or nitroso compounds, one or more polypeptide neurotransmitters, and/or one or more agents which inhibit phosphodiesterase.
The present pharmaceutical composition can be in any conventional form, such as a liquid, solid or gel. Examples of suitable liquids include sterile solutions, suspensions, and emulsions, including creams, ointments, and liposomes. For oil based or lipophilic preparations, other suitable anti-oxidants include BHT. For water based or hydrophilic preparations, other suitable anti-oxidants include ascorbic acid and its sodium and potassium salts. Preferred PEG suppositories contain a PEG which is solid at ambient or room temperature but rapidly dissolves/melts when placed on the clitoris. Good results have been achieved using isotonic aqueous solutions which contain sodium citrate.
Examples of suitable solids include polyethylene glycol (PEG), polyethylene oxide and other low melting point or water-soluble polymers including fatty acid esters made into suppositories or pellets. Examples of suitable gels include triacetin, hydroxycellulose, gels composed of water, propylene glycol, hydroxypropyl methylcellulose and any other gels which are compatible with the prostaglandin. Liposomal mixtures are particularly preferred as they tend to induce a stronger effect at a given dose of prostaglandin and stabilize the prostaglandin. A commercially available liposome to which the prostaglandin can be added is Liposyn II(trademark) 10% or 20% sold by Abbott Laboratories, North Chicago Ill. The liposomes may be prepared as either anionic or cationic liposomes depending upon the prostaglandin and any co-agent present in order to maximize the desired effect. A particularly preferred gel is lecithin organogel prepared according to H. Willimann et al, xe2x80x9cLecithin organolgel as matrix for transdermal transport of drugs,xe2x80x9d J. Pharm. Sci., vol. 81(9), pp. 871-874 (1992). This particular preparation exhibits a dramatically enhanced potency.
One may also use a gel in which one or more of the prostaglandins or co-agents is released in a controlled-released manner (i.e., released over time) to prolong the effect of the composition. For example, PGE can be formulated into a cross-linked polyethylene oxide/urethane polymer which is well tolerated by living tissues and releases the prostaglandin in a controlled release manner. Controlled release compositions are disclosed in D. H. Lewis, Controlled Release of Pesticides and Pharmaceuticals, Plenum Press, New York, 1981; and A. F. Kydonieus, Controlled Release Technologies: Methods, Theory, and Applications, CRC Press, Boca Raton, 1980, which are incorporated herein by reference.
In another preferred embodiment, the present composition is in the form of a solution in which the prostaglandin with or without a PGDH inhibitor or coagent is dissolved or suspended in 1,2,3-propanetriol triacetate, triacetin. Triacetin is a well known solvent and is commercially available from Aldrich Chemical Company, St. Louis, Mo. This composition enhances the drug potency dramatically and chemically stabilizes the prostaglandin at room temperature. Other similar short-chain triglycerides with alkyl chains from C1-6 are expected to have similar beneficial effects. These compounds are available from Sigma Chemical Company (St. Louis, Mo.).
Typically, the present pharmaceutical composition will contain the prostaglandin in a concentration such that an effective amount of the prostaglandin is delivered to the clitoris with a single application of the composition. For example, in the case of a liquid, the composition will contain sufficient prostaglandin such that an effective amount of the prostaglandin is delivered to the clitoris by application of a drop (0.01 to 0.30 ml) of the liquid. Thus, the present compositions, when in the form of a liquid will suitably contain 10 nanograms/ml to 1,500 xcexcg/ml, preferably 100 nanograms/ml to 1,000 xcexcg/ml, of the prostaglandin. In the case of a suppository, the suppository will preferably contain sufficient prostaglandin such that an effective amount of the prostaglandin is delivered to the clitoris by application of a single suppository to the clitoris. Suppositories according to the present invention typically have volumes of 0.01 to 0.30 ml, preferably 0.1 to 0.2 ml. Thus, pharmaceutical compositions according to the present invention which are in the form of a suppository will suitably contain the prostaglandin in a concentration of 10 nanograms/ml to 1,500 xcexcg/ml, preferably 100 nanograms to 1,000 xcexcg/ml. Similarly, when the composition is in the form of a gel, the gel will typically contain sufficient prostaglandin such that an effective amount of prostaglandin is delivered to the clitoris upon application of a single dose (0.01 to 0.60 ml, preferably 0.05 to 0.40 ml) of the gel to the clitoris. Thus, the gels of the present invention will suitably contain the prostaglandin in a concentration of 10 nanograms/ml to 1,500 xcexcg/ml, preferably 100 nanograms to 1,000 xcexcg/ml. Since drug dosages typically vary from person to person, repeated applications may be used to achieve the desired effect.
When the prostaglandin is prostaglandin E1, the pharmaceutical composition will suitably contain the prostaglandin E1 in an amount of 20 nanograms to 2,000 xcexcg, preferably 200 nanograms to 500 xcexcg, per unit dosage. When the prostaglandin is prostaglandin E2, the pharmaceutical composition will suitably contain the prostaglandin E2 in an amount of 0.1 nanograms to 2,000 xcexcg, preferably 1.0 nanograms to 500 xcexcg, per unit dosage.
In a third embodiment, the present invention provides kits which are useful for enhancing female sexual desire and response. The present kits are characterized as containing: (a) a means for containing a prostaglandin or pharmaceutical composition containing the prostaglandin; and (b) means for administering the prostaglandin or pharmaceutical composition containing the prostaglandin to the clitoris. The means for containing the prostaglandin or pharmaceutical composition containing the prostaglandin may be a vial, a bottle, a pouch, an envelope, a can, a tube, an atomizer, an aerosol can, etc. The means for administering the prostaglandin or pharmaceutical composition containing the prostaglandin to the clitoris may be a dropper, a swab, a stick, or the nozzle or outlet of an atomizer or aerosol can. It is to be understood that the means for administering the prostaglandin or pharmaceutical composition containing the prostaglandin to the clitoris may be connected to or a part of the means for containing the prostaglandin or pharmaceutical composition containing the prostaglandin. For example, the containing means may be an atomizer or an aerosol can, and the administering means may be the nozzle or outlet of the atomizer or the aerosol can.
Examples of preferred kits include:
A. A kit which includes a container which can hold 1 to 100 unit doses of the prostaglandin or the pharmaceutical composition containing the prostaglandin and a dropper which can dispense between 0.01 to 0.6 ml as a unit dose. The container is preferably glass, metal, or a plastic known not to adsorb hydrophobic compounds.
B. A kit which includes a container which can hold 1 to 100 unit doses of the prostaglandin or the pharmaceutical composition containing the prostaglandin with a spray or aerosol applicator to spray the prostaglandin or pharmaceutical composition onto the clitoris. The container is preferably glass, metal, or a plastic known not to adsorb hydrophobic compounds.
C. A kit which includes a tube which holds 1 to 100 unit doses of a pharmaceutical composition containing the prostaglandin, which is in the form of a cream or gel, and an applicator which can dispense a unit dose of the composition.
D. A kit which includes 1 to 100 unit doses of pellets, film or suppositories containing a pharmaceutical composition comprising the prostaglandin and each individually wrapped in foil and sealed to protect the prostaglandin from the air. The foil is preferably opaque to eliminate the degrading effects of light on the prostaglandin.
E. A kit which includes 1 to 100 unit doses of a pharmaceutical composition which comprises the prostaglandin and which have been lypholized and sealed under inert gas in an ampoule or vial. Lyophilized compositions typically exhibit a much longer shelf life than other forms and may be reconstituted close to the time of use so that degradation of the prostaglandin is minimized. The kit may also include a suitable diluent, syringe and needle, and/or alcohol swabs.
The present kits will also typically include means for packaging the container means and the administering means. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc. The present kits will also usually include written instructions which describe how to administer the prostaglandin or pharmaceutical composition containing the prostaglandin to the clitoris. It is to be understood that the written instructions may be on any of the container means, the administering means, or the packaging means, in addition to being present on a separate piece of paper.
In another embodiment, the present invention provides novel methods of diagnosing sexual dysfunction in a female. The present method of diagnosing female sexual dysfunction involves monitoring the baseline clitoral temperature of the clitoris in a female, administering a prostaglandin agent, known to cause a sexual response when applied to a clitoris, to the clitoris of said female, measuring the clitoral temperature response of said female to said administering, and comparing said clitoral temperature response of said female to that found in females not suffering sexual dysfunction.
Other features of the present invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.